1. Filed of the Invention
The present invention relates to [(1,3-dioxo-1,3-propanediyl)diimino]bisbenzoic acid derivatives which have hyaluronidase-inhibiting, anti-allergic, immunomodulating and anti-ulcerous activities, process for preparation thereof and pharmaceutical composition comprising the said derivative.
It is well known that hyaluronidase is present in various parts of living organism normally in an inactive form and act as a phlogovenic enzyme at the inflammatory site. For example, hyaluronidase has an important role in induction of I (immediate) type allergic reaction and hence the use of hyaluronidase-inhibiting drug in these pathologic conditions appears reasonable.
On the other hand, the conventional antiallergic agents such as chlorpheniramine maleate, disodium cromoglicate, tranilast etc. have a number of deficiencies such as induction of undesirable side effect, insufficiency of peroral absorption, unsatisfactoriness of therapeutic effect and so on. Also, there has been a continuous demand for the anti-ulcerous agent which has a mechanism action of approaching the causal treatment. The inventors have succeeded in developing a anti-allergic and anti-ulcerous agent which has an excellent anti-hyaluronidase activity, on the basis of a conception that hyaluronidase inhibitor is useful as a causal treatment of pathologic conditions such as a allergic disease.
2. Related Disclosures
Japanese Patent Publication (Unexamined) No. 7716/1981 discloses 2,2'-[(1, omega-dioxo-1, omega-alkane (C.sub.1-10)diyl)diimino]bisbenzoic acid as a cerebral vasospasmodic inhibitor. Japanese Patent Publication (Unexamined) No. 13660/1983 discloses [(1,3-dioxo-1,3propanediyl)diimino]bisbenzoic acid as an azo dyestuff. Australian Journal of Chemistry 36 (1983) 1133-1140 discloses dimethyl 2,2'-[(1,3-dioxo-2-phenylmethylene-1, 3-propanediyl)diimino]bisbenzoate as an intermediate for metal-complexing agent. This dimethyl ester was prepared by a method in which phenylmethylene malonic dichloride was reacted with methyl anthranilate. The said method, however, is disadvantageous and cannot be actually carried out in the commercial production. Further, 2,2'-[(1,3-dioxo-2-aryl- methylene-1,3-propanediyl)diimino]bisbenzoic acid is published by T. Satoh, H. Kakegawa, Y. Momoi, H. Matsumoto,J. Yoshinaga and J. Riku, the inventors, at VIIIth International Symposium on Medicinal Chemistry, Held in Sweden on August 27-31, 1984.